During the storyline for Grand Theft Auto: Vice City Stories, the Mendez Cartel have a big shipment coming in, which is stolen by the Vance Crime Family leaders, Victor and Lance Vance. The two mistaking the drugs for belonging to Jerry Martinez, former sergeant of Victor in the army. After finding out that the drugs belonged to the Mendez Cartel, this forces the Vance's to go and officially "explain themselves" to Diego and Armando Mendez. The Vance's lie and claim that Martinez stole the drugs while using photos off Martinez talking to the federal as he is turning states.

After doing a couple of favors for the Mendez's, Victor Vance is put in contact with Ricardo Diaz, rival drug baron, through Reni Wassulmaier who is actually an 'item' with Diego Mendez. When the Vance's are called over to the Mendez mansion they are rewarded with a death trap led by the Mendez, full of explosives. The Vance's manage to escape and declare war on the Mendez Cartel.

After several failed attempts, Armando Mendez kidnaps Louise Cassidy-Williams and Lance, Armando then kills Louise, while Victor makes his way inside the Mendez mansion, confronting and killing a flamethrower wielding Armando. Diego Mendez then escapes to the Mendez Foundation Building in Downtown. Victor, with the help of Louise's brother, Phil Cassidy, breaks into the Fort Baxter military base and steals a Hunter. Later on, he uses it to attack the remaining head, Diego.

The Hunter is shot down but Victor manages to stop at the roof and survive the explosion. Forced to search through the building to find Diego, he makes his way and finally manages it. On a confrontation on the roof, Jerry Martinez, Victor Vance and Diego Mendez fight a three-men gunfight where Victor wins and kills the other two, winning the battle.

Afterward the Mendez Cartel quickly crumbles and is non-existant by 1986. The Mendez Cartel's mansion on Prawn Island is eventually taken over by the Sharks in between 1984 and 1986, and during that interval the Mendez Building is demolished and replaced by a lower building.

The Mendez Cartel members are depicted as wearing suits, with light colored shirts underneath, as well as having a notable moustache or ponytails.
It's possible that it was the most powerful criminal organization at the time, but when their leaders were killed, the Diaz cartel quickly seized most of the drug trade in the city.